The earliest events in HIV mucosal transmission are not well defined, yet understanding these events may provide important information regarding the design of an HIV vaccine. Two features of mucosal transmission stand out. First, mucosal transmission is inefficient. Second, in the majority of newly infected individuals the virus rapidly establishes infection in gut associated lymphoid compartments. Understanding the barriers that contribute to inefficient transmission, and the role of gut lymphoid tissue as sites of viral replication represent critically important information that may aid in the design of an HIV vaccine. In order to establish infection HIV must overcome multiple structural barriers and it only achieves productive infection upon gaining access to metabolically active CD4+ T cells. This process requires that the HIV envelope protein first binds to the CD4 receptor; however, the CD4 receptor is expressed at high levels not just on metabolically activated cells, but also on resting cells, which are poor substrates for productive infection. alpha4-beta7 is an additional HIV receptor on the surface of CD4+ T cells. Alpha4beta7 is not an entry receptor; however, unlike CD4, integrin alpha4-beta7 is preferentially expressed on cells in mucosal tissues that are activated. We are testing the hypothesis that gp120 interactions with alpha4-beta7 facilitates transmission. The manner in which this occurs is not yet understood. However these interactions hold the potential to impact the design of both vaccines and therapeutic strategies that reduce or eliminate viral reservoirs.